Hydrazones of 1-amino-4-diphenyl-acetylpiperazines



United States Patent 3,294,788 HYDRAZONES 0F 1-AMINO-4-DIPHENYL-ACETYLPIPERAZINES John W. Cusic, Skokie, and Peter Yonan, Chicago, Ill.,

assignors to G. D. Searle & C0., Chicago, 113., a corporation ofDelaware N0 Drawing. Filed Apr. 21, 1964, Ser. No. 361,588 5 Claims.(Cl. 260-240) The present invention relates to a group of hydrazones of4-substituted l-aminopiperazines. More particularly, it relates tocompounds having the following general formula wherein Y is selectedfrom the group consisting of hydrogen and halogen; X is selected fromthe group consisting of hydrogen, lower alkyl, and phenyl; and Z isselected from the group consisting of lower alkyl, phenyl, tolyl,v

halophenyl, hydroxyphenyl, methylenedioxyphenyl, methoxyphenyl,cyanophenyl, pyridyl, methylpyridyl, and ferrocenyl.

The lower alkyl radicals referred to above contain up to 6 carbon atomsand can be exemplified by radicals such as methyl, ethyl, propyl, andbutyl. The halogen radicals referred to above are exemplified byfluorine, chlorine, bromine, and iodine. The halophenyl radicalsreferred to above include fluorophenyl, chlorophenyl, bromophenyl, andiodophenyl.

' The compounds of the present invention can be prepared by thecondensation of an aldehyde or a ketone with the appropriatel-substituted 4-aminopiperazine in an inert solvent. A trace of aceticacid can be included to catalyze the reaction. Although 2-p'ropanol is aparticularly useful solvent for the reaction, ethanol or other alcoholscan also be used. In addition, aromatic hydrocarbons such as benzene ortoluene are also useful as solvents in this type of a reaction although,in this case, it is desirable to remove the water from the reactionmixture as it formed. The reaction is promoted by the use of elevatedtemperatures.

Important intermediates in the above reaction are bydrazines having thefollowing general structural formula wherein Y is defined as above.Compounds of this type are prepared by reacting l-nitrosopiperazine withthe appropriate diphenylacetyl chloride to give the corresponding amideand then selectively reducing the nitroso group with an agent such aszinc and acetic acid to give the desired hydrazine.

The compounds of this invention are useful because of theirpharmacological properties. In particular, the present compounds possessanti-ulcer activity which is demonstrated by their inhibition ofulceration in the Shay rat. In addition, the present compounds possessactivity as antiat herogenic agents which is demonstrated by theirinhibition of hepatic synthesis of cholesterol. The present compoundsalso show activity as anti-bacterial agents as shown by their inhibitionof the growth of the organism Diplococcus pneumoniae.

The following examples are presented to further illustrate the presentinvention; they should not be construed quantities are indicated inparts by weight and temperatures in degrees centigrade C.).

Example 1 A solution of 70 parts of diphenylacetyl chloride in 150 partsof chloroform is added portionwise to a solution of parts oftriethylamine in 375 parts of chloroform. The addition is exothermic.When the addition is complete, 36 parts of l-nitrosopiperazine is addedto the mixture portionwise while the temperature is kept at about 6065C. The mixture is heated at reflux for an additional 3 hours and thencooled and diluted with 150 parts of chloroform. The resultantchloroform solution is washed with water and dried and the solvent isevaporated under reduced pressure to leave a residual oil which latersolidifies. The solid is then washed with ether to give1-nitroso-4-diphenylacetylpiperazine melting at about 149- 151 C.Recrystallization of this solid from a mixture of chloroform and hexanegives a product melting at about 151-152 C.

A solution is prepared from 30 parts of 1-nitroso-4-diphenylacetylpiperazine and 420 parts of glacial acetic acid and thissolution is heated to 50 C. The solution is diluted with 80 parts ofwater and then 50 parts of zinc dust is added portionwise over a periodof about 30 minutes While the temperature is maintained at about 50- 55C. Stirring at this temperature is continued for an additional 15minutes after the addition is complete. The hot mixture is then filteredand diluted with 500 parts of cold water and the resultant mixture iscooled in an ice bath while it is made alkaline with a solution of 300parts of sodium hydroxide in 750 parts of water. The resultant alkalinemixture is extracted with 3 portions of chloroform and the combinedchloroform extracts are dried and the solvent is evaporated. Ether isadded to the resultant residue whereupon crystals form. The product thusobtained is 1-amino-4-diphenylacetylpiperazine and it melts at about132133 C.

If the above procedure is repeated using l-nitrosopiperazine and4-chlorodiphenylacetyl chloride as the reactants, the product obtainedis '1amino-4-(4-ohlorodiphenylacetyl)piperazine. formula Example 2 To asolution of 3 parts of 1-arnino-4-diphenylacetylpiperazine in 32 partsof Z-propanol, there is added 1.7 parts of piperonal and a drop ofacetic acid. The resultant mixture is heated at the boiling point forabout 5 minutes and then cooled. The product which precipitates is thenseparated. It is 1-piperonylideneamino-4-diphenylacetylpiperazine and itmelts at about -141" C. This compound has the following formula Example3 If an equivalent quantity of1-amino-4-(4-chlorodiphenylacetyDpiperazine is substituted for thel-amino-4- This compound has the following diphenylacetylpiperazine andthe procedure of Example 2 is repeated, the product is1-piperonylideneamino-4-(4- chloro diphenylacetyl) piperazine.

Example 4 If an equivalent quantity of pyridine-4-carboxyaldehyde issubstituted for the piperonal and the procedure of Example 2 isrepeated, the product is1-(4-pyridylmethyleneamino)-4-diphenylacetylpiperazine melting at about163- 164 C. This compound has the following formula Example 6 Anequivalent quantity of ferrocenecarboxaldehyde is substituted for thepiperonal and the procedure of Example 2 is repeated. The productobtained is recrystallized from a mixture of benzene and hexane to givel-ferrocenylmethyleneamino-4-diphenylacetylpiperazine melting at about177-17 8 C. This compound has the following formula Example 7 A solutionof 2 parts of 1-amino-4-diphenylacetylpiperazine in 10 parts of aceticanhydride is heated on a steam bath for 1 hour. The resultant mixture isthen poured onto ice and made alkaline with dilute sodium hydroxidesolution. The alkaline mixture is extracted with chloroform and thechloroform extract is dried and concentrated. A precipitate forms whenether is added to the chloroform concentrate. This solid is separatedand recrystallized from a mixture of chloroform and ether to give1-acetylamino-4-diphenylacetylpiperazine melting at about 172-173 C. 7

What is claimed is: 1. A compound of the formula wherein Y is selectedfrom the group consisting of hydrogen and halogen and Z is selected fromthe group consisting of phenyl, hydroxyphenyl, methylenedioxyphenyl,

cyanophenyl, pyridyl, and ferrocenyl.

2. 1 piperonylideneamino 4 diphenylacetylpiperazme.

3. 1 (4 hydroxybenzylideneamino) 4 diphenylacetylpiperazine.

1 (4 pyridylmethyleneamino) 4 diphenylacetylpiperazine.

5. 1 ferrocenylmethyleneamino 4 diphenylacetylpiperazine.

References Cited by the Examiner UNITED STATES PATENTS 3,178,422 4/ 1965Cusic et al 260-240 JOHN D. RANDOLPH, Primary Examiner.

1. A COMPOUND OF THE FORMULA